Targeting tumor-infiltrating macrophages decreases tumor-initiating cells, relieves immunosuppression, and improves chemotherapeutic responses

Mitchem, Jonathan B., Brennan, Donal J., Knolhoff, Brett L., Belt, Brian A., Zhu, Yu, Sanford, Dominic E., Belaygorod, Larisa, Carpenter, Danielle, Collins, Lynne, Piwnica-Worms, David, Hewitt, Stephen, Udupi, Girish Mallya, Gallagher, William M., Wegner, Craig, West, Brian L., Wang-Gillam, Andrea, Goedegebuure, Peter, Linehan, David C. and DeNardo, David G. (2013) Targeting tumor-infiltrating macrophages decreases tumor-initiating cells, relieves immunosuppression, and improves chemotherapeutic responses. Cancer Research, 73 3: 1128-1141. doi:10.1158/0008-5472.CAN-12-2731


Author Mitchem, Jonathan B.
Brennan, Donal J.
Knolhoff, Brett L.
Belt, Brian A.
Zhu, Yu
Sanford, Dominic E.
Belaygorod, Larisa
Carpenter, Danielle
Collins, Lynne
Piwnica-Worms, David
Hewitt, Stephen
Udupi, Girish Mallya
Gallagher, William M.
Wegner, Craig
West, Brian L.
Wang-Gillam, Andrea
Goedegebuure, Peter
Linehan, David C.
DeNardo, David G.
Title Targeting tumor-infiltrating macrophages decreases tumor-initiating cells, relieves immunosuppression, and improves chemotherapeutic responses
Journal name Cancer Research   Check publisher's open access policy
ISSN 0008-5472
1538-7445
Publication date 2013-02-01
Year available 2012
Sub-type Article (original research)
DOI 10.1158/0008-5472.CAN-12-2731
Volume 73
Issue 3
Start page 1128
End page 1141
Total pages 14
Place of publication Philadelphia, United States
Publisher American Association for Cancer Research
Collection year 2013
Language eng
Abstract Tumor-infiltrating immune cells can promote chemoresistance and metastatic spread in aggressive tumors. Consequently, the type and quality of immune responses present in the neoplastic stroma are highly predictive of patient outcome in several cancer types. In addition to host immune responses, intrinsic tumor cell activities that mimic stem cell properties have been linked to chemoresistance, metastatic dissemination, and the induction of immune suppression. Cancer stem cells are far from a static cell population; rather, their presence seems to be controlled by highly dynamic processes that are dependent on cues from the tumor stroma. However, the impact immune responses have on tumor stem cell differentiation or expansion is not well understood. In this study, we show that targeting tumor-infiltrating macrophages (TAM) and inflammatory monocytes by inhibiting either the myeloid cell receptors colony-stimulating factor-1 receptor (CSF1R) or chemokine (C–C motif) receptor 2 (CCR2) decreases the number of tumor-initiating cells (TIC) in pancreatic tumors. Targeting CCR2 or CSF1R improves chemotherapeutic efficacy, inhibits metastasis, and increases antitumor T-cell responses. Tumor-educated macrophages also directly enhanced the tumor-initiating capacity of pancreatic tumor cells by activating the transcription factor STAT3, thereby facilitating macrophage-mediated suppression of CD8+ T lymphocytes. Together, our findings show how targeting TAMs can effectively overcome therapeutic resistance mediated by TICs
Keyword Cancer stem-cells
Pancreatic ductal adenocarcinoma
Breast cancer
Inflammatory monocytes
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ
Additional Notes Published online 5 December 2012.

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2013 Collection
School of Medicine Publications
 
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